1. Field of the Invention
This invention relates to a structure and method of administering precisely measured doses of a therapeutic by inhalation.
An accurate mechanism for delivering precise doses of aerosol drugs into the interior of human lungs has been an objective of many workers in the art. One of the most popular aerosol delivery devices is the propellent-driven metered dose inhaler (MDI), which releases a metered dose of medicine upon each actuation. Although these devices may be useful for many medicines, only a small variable percentage of the medicine is delivered to the lungs. The high linear speed with which the dosage leaves the device, coupled with incomplete evaporation of the propellants, causes much of the medicine to impact and stick to the back of the throat. This impacting and sticking creates a local concentration of drugs much of which is eventually swallowed. In the trade, this impact area is called a xe2x80x9chot spotxe2x80x9d and can cause local immuno-suppression and the development of fungal infections with bronchosteriods. With broncodilators, for instance, the swallowed dose can contribute to unwanted systemic side effects such as tremor and tachycardia.
MDI""s also require a degree of coordination between activation and inhalation. Many patients are incapable of this task, especially infants, small children and the elderly. In an effort to overcome some of the above limitations of MDI""s, others have interposed xe2x80x9cspacersxe2x80x9d between the conventional MDI and the patient. The primary function of these spacers is to provide extra volume to allow time for increased propellent droplet evaporation prior to inhalation and to reduce the velocity and impact of the medicine at the back of the throat. Although spacers do compensate for some of the inadequacies in the conventional MDI, it has been found that much of the medicine that may have ordinarily been deposited on the throat remains in the spacer and the total dose deposited in the lungs is small. It has been found that only approximately 8% of the medicine reaches the interior of the lung with conventional MDI""s. Approximately 13% of the medicine reaches the lung when it is equipped with a spacer.
Other workers in the art have attempted to provide a metered dose of a medicant by using dry powder inhalers (DPI). Such devices normally rely on a burst of inspired air that is drawn through the unit. However, these units are disadvantaged in that the force of inspiration varies considerably from person to person. Some patients are unable to generate sufficient flow to activate the unit. DPI""s have many of the disadvantages of MDI""s in that a large percentage of the medicant is deposited in the throat because of incomplete particle dispersion and the impact at the rear of the throat. Although pocket size MDI""s and DPI""s are very convenient they have disadvantages some of which are cited above.
Other workers in the art have refined aqueous nebulization delivery systems. Although such systems require a continuous gas compressor, making them less portable than the MDI""s and the DPI""s, many nebulizers provide a low velocity aerosol which can be slowly and deeply inhaled into the lungs. Precision of dosage delivery, however, remains a serious problem and it is difficult to determine how much medicament the patient has received. Most nebulizers operate continuously during inhalation and exhalation. Dosage is dependent on the number and duration of each breath. In addition to breath frequency and duration, the flow rate, i.e., the strength of the breath that is taken from a nebulizer can effect the particle size of the dose inhaled. The patient""s inhalation acts as a vacuum pump that reduces the pressure in the nebulizer. A strong breath can draw larger unwanted particles of medicant out of the nebulizer. A weak breath, on the other hand, will draw insufficient medicant from the nebulizer.
Electro-mechanical ventilators and devices have also been used in recent years to deliver inhalable materials to a patient. These devices permit mixing of a nebulized medicant into breathing circuit air only during pre-set periods of a breathing cycle. An example of this type of machine is the system taught by Edgar et al., in their U.S. Pat. No. 4,677,975, issued in July of 1987 where a nebulizer is connected to a chamber which in turn is connected to a mouthpiece, an exhaust valve, and an inlet valve. A breath detector and timer are used to deliver nebulized materials to the patient during a portion of the breathing cycle. However, in Edgar and others of this type, the patient""s intake strength can effect the nebulizer operation with many of the consequences heretofore mentioned. Moreover, the amount of nebulized material delivered in each breath can vary significantly, contributing to inaccurate total dosages. In a modification of Edgar et al. (Elliott, et al. (1987) Australian Paediatr. J. 23:293-297), filling of the chamber with aerosol is timed to occur during the exhalation phase of the breathing cycle so that the patient is not inhaling through the device during nebulization. This design, however, requires that the patient maintain a constantly rhythmic breathing pattern into and out of the device, which is inconvenient and can contaminate the device with oval microbes. Moreover, no provision is made on the devices to efficiently capture the aerosol in the chamber so that as many as 80 breaths or more must be taken to obtain a dose of medication.
The delivery of therapeutic proteins and polypeptides by inhalation presents additional problems. Many protein drugs are produced recombinantly and can thus be very expensive. It is therefore important that loss of a protein drug within the delivery device be reduced or preferably eliminated. That is, substantially all drug initially charged within the device should be aerosolized and delivered to the patient without loss within the device or released externally of the device. The protein drugs should further be delivered to the patient under conditions which permit their maximum utilization. In particular, protein drugs should be completely dispersed into small particles in the preferred 1 xcexcm to 5 xcexcm size range which is preferentially delivered to the alveolar region of the lungs. The amount of protein drug delivered to the patient in each breath must also be precisely measured so that the total dosage of drug can be accurately controlled. Finally, it will be desirable to permit the delivery of highly concentrated aerosols of the protein drug so that the number of breaths required for a given dosage can be reduced, thus increasing accuracy and reducing the total time required for administration.
2. Description of the Background Art
U.S. Pat. Nos. 4,926,852 and 4,790,305, describe a type of xe2x80x9cspacerxe2x80x9d for use with a metered dose inhaler. The spacer defines a large cylindrical volume which receives an axially directed burst of drug from a propellant-driven drug supply. U.S. Pat. No. 5,027,806, is an improvement over the ""852 and ""305 patents, having a conical holding chamber which receives an axial burst of drug. U.S. Pat. No. 4,624,251, describes a nebulizer connected to a mixing chamber to permit a continuous recycling of gas through the nebulizer. U.S. Pat. No. 4,677,975, is described above. European patent application 347,779 describes an expandable spacer for a metered dose inhaler having a one-way valve on the mouthpiece. WO 90/07351 describes a dry powder oral inhaler having a pressurized gas source (a piston pump) which draws a measured amount of powder into a venturi arrangement.
The present invention provides methods and apparatus for producing an aerosolized dose of a medicament for subsequent inhalation by a patient. The method comprises first dispersing a preselected amount of the medicament in a predetermined volume of gas, usually air. The dispersion may be formed from a liquid, for example by injecting an air stream through a liquid reservoir of the drug, or from a dry powder, for example by drawing the powder into a flowing air stream from a reservoir using a venturi or other dispersion nozzle. The present invention relies on flowing substantially the entire aerosolized dose into a chamber which is initially filled with air and open through a mouthpiece to the ambient. The aerosolized dose of medicament flows into the chamber under conditions which result in efficient displacement of the air with the aerosolized material. By xe2x80x9cefficient displacement,xe2x80x9d it is meant that at least 40% by weight of the aerosolized material entering the chamber will remain aerosolized and suspended within the chamber, thus being available for subsequent inhalation through the mouthpiece. It is further meant that very little or none of the aerosolized material will escape from the chamber prior to inhalation by the patient. Efficient displacement of air and filling of the chamber can be achieved by proper design of the chamber, as discussed below.
After the aerosolized medicament has been transferred to the chamber, the patient will inhale the entire dose in a single breath. Usually, the total volume of aerosolized medicament and air within the chamber will be substantially less than an average patient""s inspiratory capacity, typically being about 100 ml to 750 ml. In this way, the patient can first inhale the entire amount of drug present in the dose and continue in the same breath to take in air from the ambient which passes through the chamber and which helps drive the medicament further down into the alveolar region of the lungs. Conveniently, the steps of aerosolizing the medicament, filling the chamber, and inhalation of the chamber contents may be repeated as many times as necessary to provide a desired total dosage of the medicament for the patient.
Apparatus according to the present invention comprise both a dispersion device for aerosolizing the medicament, either from a liquid or dry powder formulation of the medicament, and a chamber having an air inlet and patient mouthpiece for receiving the aerosolized medicament from the dispersion device. The chamber is designed and connected to the dispersion device in such a way that the aerosolized medicament will flow into the chamber and efficiently displace the internal air volume, as described above. The volume of the chamber will be at least as large as the maximum expected volume of aerosolized medicament to be transferred from the dispersion device. Usually, the chamber volume will be greater than the aerosol volume in order to reduce losses through the mouthpiece, with exemplary chamber volumes being in the range from 100 ml to 750 ml, as described above. The volume of aerosolized medicament will usually be in the range from 50 ml to 750 ml when the dispersion device is a liquid nebulizer and from 10 ml to 200 ml when the dispersion device is a dry powder disperser, as described in more detail below. In order to enhance efficient filling, the chamber will preferably define an internal flow path so that the entering aerosolized medicament will follow the path and displace air within the chamber without substantial loss of the medicament through the mouthpiece. Alternatively, the chamber may include a baffle which acts to entrap a high velocity aerosol, particularly those associated with dry powder dispersions.
In a preferred aspect, the chamber is generally cylindrical and is connected to the dispersion device by a tangentially disposed aerosol inlet port located at one end of the cylinder The mouthpiece is then located at the opposite end of the cylinder, and aerosolized medicament flowing into the chamber will follow a generally vortical flow path defined by the internal wall of the chamber. By also providing an ambient air inlet at the same end of the cylindrical chamber, the patient can first inhale the medicament and thereafter breath in substantial amounts of ambient air, thus sweeping the interior of the chamber to efficiently remove substantially all aerosolized medicament present and help drive the medicament further into the patient""s lungs.
In further preferred aspects, the ambient air inlet of the chamber will be protected, typically through a one-way valve structure which permits air inflow but blocks aerosol outflow, so that aerosol will not be lost as it enters the chamber. The chamber may also comprise vortical baffles, typically in the form of an axially aligned tube or conical cylinder within the interior of the chamber, to restrict dispersion of the aerosol within the chamber and improve delivery efficiency.
In an alternate preferred aspect, the chamber is generally cylindrical with an axially oriented aerosol inlet port located at one end. The mouthpiece is located at the other end of the cylinder, and an internal baffle is located between the aerosol inlet and the mouthpiece to prevent direct passage of the aerosol to the mouthpiece (which could result in loss of medicament well before the chamber has been efficiently filled). The internal baffle is preferably hemispherical in shape with a concave surface oriented toward the aerosol inlet. Such a construction has been found particularly useful in initially containing dry powder dispersions which are often introduced using a high velocity (frequently sonic) gas stream. The chamber further includes a tangential ambient air inlet port disposed in the chamber wall between the aerosol inlet and the internal baffle. By inhaling through the mouthpiece, the patient is able to establish a vortical flow of ambient air which will sweep the contained aerosol past the baffle and through the mouthpiece.
In yet another aspect of the present invention, the apparatus for producing aerosolized doses of a medicament comprises the dispersing device, means for delivering pressurized gas to the dispersing device, the aerosol chamber, and a controller capable of selectively controlling the amount of pressurized air delivered to the dispersing device in order to produce the desired single doses of medicament and deliver said doses to the chamber. The controller may include means for timing the actuation of a compressor or means for controlling the amount of gas released from a pressurized cylinder, as well as a mechanism for counting and displaying the number of doses delivered from the chamber during a particular period of use. Still further, the controller may include a microprocessor and a keypad for inputting information to the microprocessor.
In exemplary devices, the controller may comprise a timer connected to selectively actuate a valve, such as a solenoid valve, on a gas cylinder. Alternatively, the timer may turn on and off an air compressor to regulate the amount of air delivered to the dispersing device. In portable and hand-held apparatus, the controller may simply be a release button or mechanism that actuates a spring or air driven piston to deliver a specific amount of gas. The controller could also be a metered valve which could release a fixed amount of liquid propellant to the dispersing device (in a manner similar to a metered dose inhaler).
The method and the apparatus of the present invention are particularly effective for delivering high value drugs, such as polypeptides and proteins, to a patient with minimal loss of the drug in the device. Moreover, the method and device provide for a very accurate measurement and delivery of the doses, while employing relatively simple and reliable equipment. Further advantages of the present invention include the ability to vary the total dosage delivered, either by controlling the number of breaths taken or by controlling the amount of medicament in each breath. Still further, the method and device of the present invention permit the delivery of relatively concentrated doses of the medicament in order to reduce the amount of time and number of breaths required for the delivery of a total dosage of the medicament, particularly when using dry powder medicament formulations.